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Stille Coupling ReactionRebecca C. Deocampo

Abstract. The Stille Coupling is a versatile C-C bond forming reaction

between stannanes and halides or pseudohalides, with very few limitationson the R-groups. The mechanism of the Stille reaction is one of the most 

extensively studied pathways for coupling reactions. The basic catalytic

cycle, as seen below, involves an oxidative addition  of a halide  or 

 pseudohalide to a palladium catalyst , transmetalation of with an organotin

reagent , and reductive elimination of to yield the coupled product and the

regenerated palladium catalyst.

 

Introduction

 The Stille reaction, or theMigita-Kosugi-Stille coupling, is a

chemical reaction  widely used in

organic synthesis  which involves

the coupling of an organotin

compound  (also known as

organostannanes) with a variety of 

organic electrophiles via palladium-

catalyzed coupling reaction

 

Stille reactions remain one of the

most via!le methods for the

formation of "#" !onds in organic

chemistry Their use has !een

highlighted in various areas,

including countless elegant natural

product syntheses, material

science, and in synthetic

methodology

 The Stille cross-coupling reaction of 

organohalides with organotin

compounds has !een proven to !e

a useful synthetic method for

car!on#car!on !ond formation in

organic synthesis "onse$uently,

many e%ective palladium catalytic

systems have !een developed for

Stille cross coupling reaction

&enerally, the com!ination of 

palladium catalysts with various

phosphine ligands results in

e'cellent yields and high eciencyowever, phosphine ligands and

their palladium comple'es are

often air-sensitive and are o!*ect to

+#" !ond degradation at elevated

temperature Thus, the use of other

supporting ligands for the Stille

cross-coupling reaction emerged as

an attractive alternative to the

phosphine ligands

 The Stille "oupling is a

versatile "-" !ond forming reaction

!etween stannanes and halides or

pseudohalides, with very few

limitations on the -groups ell-

ela!orated methods allow the

preparation of di%erent products

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from all of the com!inations of 

halides and stannanes depicted

!elow The main draw!ack is the

to'icity of the tin compounds used,

and their low polarity, which makes

them poorly solu!le in waterStannanes are sta!le, !ut !oronic

acids and their derivatives undergo

much the same chemistry in what

is known as the Suzuki "oupling

.mprovements in the Suzuki

"oupling may soon lead to the

same versatility without the

draw!acks of using tin compounds

"onvenient electrophiles and

stannanes/

Mechanism

 The mechanism of the Stille

reaction is one of the most

e'tensively studied pathways for

coupling reactions The !asic

catalytic cycle, as seen !elow,

involves an o'idative addition of ahalide  or pseudohalide to a

palladium catalyst, transmetalation

of with an organotin reagent, and

reductive elimination  of to yield

the coupled product and the

regenerated palladium catalyst

owever, the detailed mechanism

of the Stille coupling is e'tremely

comple' and can occur vianumerous reaction pathways 0ike

other palladium-catalyzed coupling

reactions, the active palladium

catalyst  is !elieved to !e a 12-

electron +d(3) comple', which can

!e generated in a variety of ways

1.xidative !ddition

4or most sp5-hy!ridized

organohalides, a concerted three-

center o'idative addition to this 12-

electron +d(3) comple' is

proposed This process gives the

cis-tetravalent  16-electron +d(..)

species .t has !een suggested the

presence of anionic ligands, such

as 78c, accelerate this step !y the

formation of 9+d(78c)(+:)n;<,

making the palladium species more

nucleophillic

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owever, despite normally forming

a cis-intermediate after a

concerted o'idative addition, this

product is in rapid e$uili!rium withits trans-isomer, which is

thermodynamically  more sta!le

 This cis#trans isomerism  is a

complicated process which involves

at least four concurrent

mechanisms, two of which are

autocatalyzed  and two which are

assisted !y solvent  association to

the metal

". Transmetalation

 The transmetalation  of the

trans  intermediate from the

o'idative addition step is !elievedto proceed via a variety of 

mechanisms depending on the

su!strates and conditions The

most common type of  

transmetalation for the Stille

coupling involves an associative

mechanism This pathway implies

that the organostannane, normally

a tin  atom !onded to an allyl,

alkenyl, or aryl group, cancoordinate to the palladium via one

of these dou!le !onds This

produces a =eeting pentavalent,

1>-electron species, which can

then undergo ligand detachment to

form a s$uare planar  comple'

again ?espite the organostannane

!eing coordinated to the palladium

through the 5  group, 5 must !e

formally transferred to the

palladium (the 5-Sn !ond must !e

!roken), and the @ group must

leave with the tin, completing thetransmetalation This is !elieved to

occur through two mechanisms

4irst, when the organostannane

initially adds to the trans metal

comple', the @ group can

coordinate to the tin, in addition to

the palladium, producing a cyclic

transition state Areakdown of this

adduct results in the loss of :Sn-@

and a trivalent palladium  comple'

with 1  and 5  present in a cis

relationship 8nother commonly

seen mechanism involves the same

initial addition of the

organostannane to the trans

palladium comple' as seen a!oveB

however, in this case, the @ group

does not coordinate to the tin,

producing an open transition state

8fter the C-car!on  relative to tinattacks the palladium, the tin

comple' will leave with a net

positive charge .n the scheme

!elow, please note that the dou!le

!ond coordinating to tin denotes

5, so any alkenyl, allyl, or aryl

group 4urthermore, the @ group

can dissociate at any time during

the mechanism and !ind to the SnD

comple' at the end ?ensityfunctional theory  calculations

predict that an open mechanism

will prevail if the 5 ligands  remain

attached to the palladium and the

@ group leaves, while the cyclic

mechanism is more pro!a!le if a

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ligand dissociates prior to the

transmetalation ence, good

leaving groups such as tri=ates in

polar solvents favor the former,

while !ulky phosphine ligands  will

favor the latter

8 less common pathway for

transmetalation  is through a

dissociative or solvent assisted

mechanism ere, a ligand from

the tetravalent palladium species

dissociates, and a coordinatingsolvent can add onto the

palladium hen the solvent

detaches, to form a 12-electron

trivalent intermediate, the

organostannane  can add to the

palladium, undergoing an open or

cyclic type process as a!ove

#. Reduction $limination

.n order for 1-5  to

reductively eliminate, these groups

must occupy mutually cis

coordination sites 8ny trans-

adducts must therefore isomerize

to the cis  intermediate or the

coupling will !e frustrated 8

variety of mechanisms e'ist for

reductive elimination and these are

usually considered to !e concerted

4irst, the 16-electron tetravalent

intermediate from thetransmetalation  step can undergo

unassisted reductive elimination

from a s$uare planar comple' This

reaction occurs in two steps/ Erst,

the reductive elimination is

followed !y coordination of the

newly formed sigma !ond !etween

1  and 5  to the metal, with

ultimate dissociation yielding the

coupled product

 The previous process, however, is

sometimes slow and can !e greatly

accelerated !y dissociation of a

ligand to yield a 12-electron  T

shaped intermediate This

intermediate can then rearrange to

form a F-shaped adduct, which can

undergo faster reductive

elimination

4inally, an e'tra ligand can

associate to the palladium to form

an 1>-electron trigonal !ipyramidal

structure, with 1 and 5 cis to each

other in e$uatorial positions Thegeometry of this intermediate

makes it similar to the F-shaped

a!ove

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 The presence of !ulky ligands  can

also increase the rate of  

elimination 0igands such as

phophines  with large !ite angles

cause steric repulsion  !etween 0

and 1  and 5, resulting in theangle !etween 0 and the groups

to increase and the angle !etween

1  and 5  to hence decrease,

allowing for $uicker reductive

elimination

Applications

 The Stille reaction has !een

used in the synthesis of a variety of 

polymers owever, the most

widespread use of the Stille

reaction is its use in organic

syntheses, and speciEcally, in the

synthesis of natural products

%atural &roduct Total Synthesis

7vermanGs  1H-step

enantioselective  total synthesis  of 

$uadrigemine " involves a dou!le

Stille cross metathesis  reaction

 The comple' organostannane is

coupled onto two aryl iodide

groups 8fter a dou!le eck

cyclization, the product is

achieved

+anekGs :5 step enantioselective

total synthesis  of ansamycinanti!iotic  (D)-mycotrienol makes

use of a late stage tandem Stille

type macrocycle coupling ere,

the organostannane has two

terminal tri!utyl tin groups

attacked to an alkene This

organostannane IstichesJ the two

ends of the linear starting material

into a macrocycle, adding the

missing two methylene units in the

process 8fter o'idation of the

aromatic core with ceric

ammonium nitrate  ("8) and

deprotection  with hydro=uoric acid

yields the natural product in L2

yield for the : steps

Stephen 4 Martin  and coworkersG

51 step enantioselective total

synthesis of the manzamine

antitumor alkaloid .rcinal 8 makes

use of a tandem one-pot

StilleN?iels-8lder reaction 8n

alkene group is added to vinyl

!romide, followed !y an in situ

?iels-8lder  cycloaddition  !etween

the added alkene and the alkene in

the pyrrolidine ring

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umerous other total syntheses

utilize the Stille reaction, including

those of o'azolomycin, lankacidin

", onamide 8, calyculin 8, lepicidin8, ripostatin 8, and lucilactaene

 The image !elow displays the Enal

natural product, the organohalide

(!lue), the organostannane (red),

and the !ond !eing formed (green

and circled) 4rom these e'amples,

it is clear that the Stille reaction

can !e used !oth at the early

stages of the synthesis

(o'azolomycin and calyculin 8), at

the end of a convergent route

(onamide 8, lankacidin ", ripostatin

8), or in the middle (lepicidin 8 and

lucilactaene) The synthesis of 

ripostatin 8 features two

concurrent Stille couplings followed

!y a ring-closing metathesis The

synthesis of lucilactaene features a

middle su!unit, having a !orane on

one side and a stannane on the

other, allowing for Stillereactionfollowed !y a su!se$uent

Suzuki coupling

References

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MB "ooper, A 8B ?oty, P 0B0u, F 7rg +roc es ?ev

533:, R, 6R6

• S + Mee, O 0ee, P Q

Aaldwin,  !ngew. Chem. 'nt.

$d., 2004, (#, 11:5-11:6

• 0ere!ours, 8 "amacho-

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Shanmugasundaram, -M

"hang, "- "heng,

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5>:2